Dolastatins have been isolated from a mollusk, Dolabella auricularia, (sea hare) from the Indian Ocean. The linear peptide Dolastatin-10 and the desipeptide Dolastatin-15 have shown most promising antiproliferative activities. Dolastatin-10 has a linear structure of 4 amino acids linked to a complex primary amine. Three of its amino acids (dolavaline, dolaisoleucine, and dolaproline) and its terminal amine (dolaphenine) are unique to the mollusk from which it was isolated. The inhibition of cell proliferation and induction of apoptosis in malignant cell lines by dolastatins are mediated through interactions with tubulin, resulting in the alteration of microtubule function. Dolastatins also exert cytotoxic effects in animals bearing intraperitoneal tumors. However, phase I and II clinical trials utilizing Dolastatin-10 did not demonstrate any responses in a variety of solid tumors and soft tissue sarcomas (Von Mehren et al, Sarcoma 2004; 8: 107). Dolastatin-15 showed severe side effects such as arterial hypertension and myocardial infarction. The low yields of chemical synthesis of dolastatins, together with their poor water solubility have motivated the synthesis and evaluation of new synthetic peptides. TZT-1027 is a synthetic tetrapeptide derivative of Dolastatin-10 with potent antitumor activity. It has a broader range of antitumor activity in vitro and in vivo against a variety of tumors including those that are taxane- and vincristine-resistant. Although some evidence of activity was observed in Phase I studies, no activity of TZT-1027 was observed in the Phase II trials (Patel et al, Cancer 2006; 107: 2881). Despite the side effects and toxicity, the mechanism of action of these molecules, make them attractive leads for developing new anti-cancer therapy, especially in combination with other anticancer drugs.